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Gastrointestinal Tolerability and Pharmacokinetics (blood levels) of the New 625 mg Nelfinavir Tablets
By Jules Levin
  At the 4th Intl Workshop on Clinical Pharmacology of HIV Therapy (March 27-29, Cannes, France) Roche researchers presented 3 studies exploring the pharmacokinetics (blood levels) & bioequivalence, and the gastrointestinal tolerability of the new nelfinavir 625 mg film-coated tablets in comparison with nelfinavir 250 mg film-coated tablets (Viracept) in healthy subjects and in HIV+ individuals. The workshop abstracts as reported by the authors follow.
The link immediately below will take you to a 6,000 word report on the proceedings at this Workshop was written for NATAP by Peter Anderson, PharmD, University of Colorado. This comprehensive report includes several very interesting topics: the effect on blood levels of 3 HIV drugs (nevirapine, nelfinavir, and ritonavir) in HCV-infected individuals; a report finding atazanavir blood levels were decreased by 25% after tenofovir was added; nevirapine levels by gender; toxicities and drug levels; drug levels, efficacy & TDM (therapeutic drug monitoring); drug levels & genetic differences.
A new formulation of nelfinavir (Viracept) containing 625 mg per tablet has been developed, reducing the pill count from 10 to 4 pills daily. This will improve convenience and adherence for patients. The Food and Drug Administration announced last week that they approved the new nelfinavir formulation for commercial availability in the pharmacy.
Nelfinavir in Healthy Volunteers
Gastrointestinal (GI) side effects are fairly common with HIV antiretroviral medications. Kaeser et al (Roche, Basel, Switzerland; abstract 41) reported on a comparison of the 250 mg and 625 mg formulations for GI tolerability and nelfinavir exposure in a multiple dose, randomized cross-over study in 48 (45 male/3 female) healthy volunteers. Nelfinavir 1250 mg twice daily was administered for 7 days with each formulation, separated by a 14 day washout of drug. On day 7 in each period, nelfinavir plasma (blood) levels were determined in the morning at trough (lowest levels) and 3.5 hours post dose. Subjects kept a stool diary (frequency, urgency, stool type) throughout the study. The primary endpoint was the incidence of moderate or severe diarrhea based on modified ACTG definitions. A secondary parameter, "GI-upset", was classifiedas 1 or more occurrences of loose stools (Bristol stool score 6-7 on a scale of 1-7), or severe fecal urgency (score 3-4 on a scale of 0-4) during treatment.
47 subjects completed both treatments, and 1 completed the 625 mg formulation treatment only. With both formulations only cases of mild diarrhea were found. "GI-upset" was detected in 23/48 (48%) of subjects on the 625mg formulation compared to 34/47 (72%) subjectson the 250mg formulation. Median (min-max) nelfinavir plasma concentrations for the 250mg and 625mg formulation were 1350 (401-4350) ng/mL and 1380 (576-6380) ng/mL at pre-dose, and 2820 (759-6310) and 3510 (1010-6660) at 3.5 hours post-dose. The authors reported that both formulations were generally well tolerated.
The authors concluded there were no incidences of moderate or severe diarrhea with either treatment. The new 625mg formulation provided about 30% higher nelfinavir plasma concentrations at around Cmax (highest drug levels after taking drug), but was associated with markedly less signs of "GI-upset" compared wit the 250 mg formulation.
Bioequivalence Found Between the 250 mg and new 625 mg Nelfinavir Formulations
Charoin et al (Roche, Basel, Switzerland, abstract 42) reported findings from a study comparing the bioequivalence of the two formulations of nelfinavir in a fed state. This was a single dose, randomized cross-over study in 52 healthy male volunteers (92% caucasian). Each formulation was administered at 1250mg after an 800 kcal standard breakfast, separated by a 4-10 day washout. Nelfinavir concentrations were determined by LC-MS/MS in plasma samples collected over 24 hours. AUC (area under the curve: the total amount of drug in blood during dosing period) and Cmax were subjected to an analysis of variance, and the effect ratios with corresponding 90% confidence intervals were calculated. Further, nelfinavir metabolite M8 pharmacokinetics were established (LC-MS/MS), and all subjects were genotypes for CYP2C19 activity, by which M8 formation is catalyzed.
50 subjects completed both treatments, and 2 completed only the reference treatment. For nelfinavir, bioequivalence was established with an effect ration of (90% CI) 95% [87%, 103%] for AUC and 101% [94%, 109%] for Cmax. Genotyping revealed two poor CYP2C19 metabolizers (1 caucasian, 1 oriental), in whom M8 concentrations were not quantifiable or close to the detection limit of 1 ng/mL. In the remaining subjects, M8 AUC and Cmax were about 25% of the nelfinavir exposures. Both single dose formulations were well tolerated.
The authors concluded that bioequivalence of the new 625mg formulation with the 250mg tablet at a single dose of 1250mg was confirmed after administration in fed state. The predominantly Caucasian study population comprised two poor CYP2C19 metabolizers which was well in line with a caucasian population representing on average 3-5% poor CYP2C19 metabolizers.
GI-Tolerability and Pharmacokinetics (blood levels) of the 625 mg Nelfinavir Tablet Found Compared to 250 mg Nelfinavir Tablet
Nieto-Cisneros et al (abstract 43, see authors below)) reported on a study of the GI tolerability and pharmacokinetics of the new Roche/Agouron nelfinavir 625mg tablets in comparison with nelfinavir 250mg tablets in HIV+ individuals.
The new 625mg nelfinavir tablet contains 400mg of the excipient poloxamir 188 to accommodate the high nelfinavir drug load. This open label inter patient exploratory study in HIV+ individuals assesses the gastrointestinal tolerability of the 625 mg nelfinavir formulation in patients switching from the 250mg tablet and patients initiating nelfinavir, who are either are either antiretroviral (ART) naive or ART-experienced. Nelfinavir 1250mg twice daily (bid) was given for two weeks using the commercial 250mg tablet followed by 4 weeks with the 625mg tablet NFV formulation. The primary endpoint of the study was defined by the incidence of moderate or severe diarrhea (ACTG) and "GI-upset" which is classified as 1 or more occurrences of loose stools (worst Bristol stool score 6-7), or severe fecal urgency (worst score 3-4) during treatment. Nelfinavir trough levels were determined by HPLC for both formulations. Preliminary analysis of 82 patients (62 ‘switch’ and 20 ‘new’) who completed both treatments show the incidence of moderate or severe diarrhea in switch patients to be 1.7% using the 625mg formulation compared to 9.7% using the 250mg NFV. GI-upset overall improved by 3%with the 625mg tablet. Diarrhia was absent in 46/59 (78%) switch patients receiving the 625mg NFV tablet compared with 30/62 (48%) receiving the 250mg tablet. No patient had severe diarrhea while on the 625mg tablet. Mean NFV and M8 trough concentrations for the 250mg and 625mg formulation were 1989.6 ng/mL and 500.87 ng/mL, and 1747.8 ng/mL and 325.85 ng/mL after the last two doses.
The authors concluded that patients on 625mg nelfinavir formulation showed improved GI-tolerability over a 4-week period when compared with the 250mg NFV. The new 625mg formulation provided comparable nelfinavir plasma concentrations with markedly less GI upset.
L Nieto-Cisneros1, M Johnson2, a Horban3, K Arasteh4, J Gonzalez-Garcia5, S Proll6, R Foreman7, and T Meuller (1Hospital General, Mexico City, Mexico; 2 Royal Free Hospital, London, UK; Wojewodzki Szital Zokony, Warsaw, Poland; 4Auguste-Viktoria Hospital, Berlin, Germany; 5Hospital Universitario La Paz, Madrid, Spain; 6+7Roche, Welwyn, UK; 8SFR-Statistics For Research, Basel, Switzerland
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